Background Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. Materials and Methods Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post‐CBT treatment using the Lugano criteria. Secondary aims included progression‐free survival (PFS), duration of response, and overall survival (OS). Results Eighty‐one patients were included. Seventy‐two percent had stage III–IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post‐CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post‐CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post‐CBT regimen. Conclusion In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post‐CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. Implications for Practice Novel, life‐prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment‐related toxicity and thus improve patient quality of life. This study investigated the outcome of checkpoint blockade therapy on subsequent treatment for patients with relapsed and refractory Hodgkin lymphoma in a large, multicenter, retrospective analysis.